The Application Of Monosaccharide As Chiral Pool For The Preparation Of Pharmaceutical Intermediates

Carbohydrates are extensively used as chiral pool in enantioselective synthesis of chiral pharmaceutical intermediates, which is one of important fields for the carbohydrate chemistry research. This thesis, focusing on atom economic and environment-friendly development requirements of modern synthetic chemistry, make full use of the carbon chain and chiral center of the monosaccharide to synthesize 1-deoxynojirimycin, anhydroalditols, chiral building blocks of side chain of stains and chiral amino alcohol catalysts of the preparation of the second alcohols. Main contents of the thesis are as follows:1) 2,3,4,6-tetra-O-benzyl-1,5-di-O-mesyl-D-alditols underwent double SN2 nucleophilic displacement reaction with amine to afford N-alkyl-L-1-deoxynojirimycin, the controlling factors of the reaction between intramolecular and intermolecular SN2 nucleophilic substitution ring closure reaction were investigated, which included dimesylates, amines, the temperature and alkalinity of the reaction. The difficult degree of the reaction of the bismesylates showed this trend:galatcose-> glucose-> mannose-derivatives; The difficult degree of the reaction of amines show this trend:NH2CH2CH2OH> CH2=CHCH2NH2> CH3(CH2)3NH2.2) Under the system of formate, amine and NaBH3CN,2,3,4,6-tetra-O-benzy1-1,5-dicarbonyl glucitol was cyclized by "one pot" reductive amination to afford N-Butyl-2,3,4,6-tetra-O-benzyl-1-deoxynojirimycin and 2,3,4,6-tetra-O-benzyl miglitol. The method was efficient, economical, safe and simple.3) After the detailedly studies on the stereoselectivity of debenzylating cycloetherification reaction of 2,3.4,6-tetra-O-benzy1-1,5-di-O-mesyl-D-alditols, 2,3,4.6-tetra-O-benzy1-1-O-tosyl-D-alditols and 3,4,5,7-tetra-O-benzy1-1,2-dideoxy-hept-1-enitols, indicating that the stereoselectivity of the reaction was dependent on the steric hindrance of the substitution. we applied the method to synthesize anhydroalditols and its derivatives in the excellent yields and high selectivities. avoiding the resolution of enantiomers. 4) Comparing chiral centers of glucose, galactose with those of side chain of stains, we designed the synthetic route to obtain two kinds of chiral building blocks from glucose and galactose:3,5-dideoxy-1,2-O-isopropylidene-6-O-triphenlmethyl-a-D-glucofuranose(the yield 21%) and (2S,4R)-4-O-benzoyloxy-5-hexene-1,2-diol(the yield 22%). These research provided good foundation for exploring a practical and high efficient synthesis of side chain of stains.5) Referring to literature, we designed five kinds of systematically tuned chiral amino alcohol catalysts from glucose, galactose and xylose. The structure-activity relationship of the catalysts in the asymmetric addition of diethylzinc to benzaldehyde was investigated, which showed that the benzyloxy on the ring of THF-based catalysts could change the enantioselectivity, the enantioselectivity of the 1,2-O-isopropylidene-a-D-xylofuranose-based catalysts was dependent on the positions of the alkylamino and hydroxyl.